Outside-in signaling by femoral cuff
injury induces a distinct vascular lesion in adipose triglyceride lipase knockout mice
Hirotsugu Noguchi1,2*, Sohsuke Yamada1,3*, Ken-ichi Hirano4, Satoshi Yamaguchi4, Akira Suzuki4, Xin Guo3, Nobuhiro Zaima5,6, Ming Li4, Kunihisa Kobayashi7, Yoshihiko Ikeda8, Toshiyuki Nakayama1 and Yasuyuki Sasaguri1
1Department of Pathology, School of Medicine, University of Occupational and Environmental Health, 2Department of Pathology, Field of Oncology, Graduate School of Medical and Dental Sciences, Kagoshima University, 3Department of Pathology and Laboratory Medicine, Kanazawa Medical University, 4Laboratory of Cardiovascular Disease, Novel, Non-invasive, and Nutritional Therapeutics (CNT) and Triglyceride Research Center (TGRC), Department of Triglyceride Science, Graduate School of Medicine, Osaka University, 5Department of Applied Biological Chemistry, Graduate School of Agriculture, Kindai University, 6Agricultural Technology and Innovation Research Institute, Kindai University, 7Department of Endocrinology and Diabetes Mellitus, Fukuoka University Chikushi Hospital and 8Department of Pathology, National Cerebral and Cardiovascular Center, Osaka, Japan
*these authors equally contributed to this work
Corresponding Author: Ken-ichi Hirano, Laboratory for Cardiovascular Disease, Novel, Non-invasive, and Nutritional Therapeutics (CNT) and Triglyceride Research Center (TGRC), Department of Triglyceride Science, Graduate School of Medicine, Osaka University, 6-2-3, Furuedai, Suita, Osaka 565-0874, Japan. e-mail: khirano@cnt-osaka.com
Summary. Genetic deficiency of adipose triglyceride lipase (ATGL), a rate-limiting enzyme for intracellular triglyceride (TG) hydrolysis, causes TG-deposit cardiomyovasculopathy (TGCV), a recently identified rare cardiovascular disorder (ORPHA code: 565612) in humans. One of the major characteristics of TGCV is a novel type of diffuse and concentric coronary atherosclerosis with ATGL-deficient smooth muscle cells (SMCs). Patients with TGCV have intractable coronary artery disease. Therefore, it is crucial to investigate the mechanisms underlying vascular lesions in ATGL deficiency using animal models. Cuff injury is an experimental procedure to induce vascular remodeling with neointimal formation with SMCs after placing a cuff around the adventitial side of the artery without direct influence on endothelium. We report the effect of cuff injury on femoral arteries of ATGL-knockout (ATGL–/–) mice. Cuff-induced concentric neointimal formation with migrating SMCs was exacerbated in ATGL–/– mice, mimicking atherosclerotic lesions in patients with TGCV. In the media, cell death of SMCs and loss of elastic fibers increased. Perivascular infiltrating cells expressing tumor necrosis factor-α (TNF-α) were more prominent in ATGL–/– mice than in wild-type (WT) mice. In Boyden chamber experiments, a greater number of ATGL–/– SMCs migrated in response to TNF-α compared to WT SMCs. These data, for the first time, demonstrated that outside-in signaling by cuff-induced neointimal formation where paracrine stimuli from adventitial infiltrating cells may lead to neointimal formation and mediolysis in ATGL-deficient conditions. Cuff injury might be a valuable model for understanding the mechanisms underlying the development of atherosclerotic lesions in patients with TGCV. Histol Histopathol 36, 91-100 (2021)
Key words: Adipose triglyceride lipase, Cuff injury, Outside-in signaling, Smooth muscle cell, Triglyceride deposit cardiomyovasculopathy
DOI: 10.14670/HH-18-285
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©The Author(s) 2021. Open Access. This article is licensed under a Creative Commons CC-BY International License. |
